Substantial evidences have shown that cholesterol synthesis is an important metabolic process which is intimately related to the control of cellular proliferation and expression of several membrane associated functions. However the mechanism through which cholesterol synthesis is regulated is not fully understood. It is generally accepted that the rate-limiting step in the sterol synthetic pathway is the generation of mevalonate, an intermediate metabolite catalized by 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase. We reason, therefore, that investigation of the mechanism by which the activity of HMG-CoA reductase is regulated is necessary not only to understand the control of sterol synthesis but the regulation of cell growth and proliferation. Several oxygenated derivatives of cholesterol, e.g., 25-hydroxycholesterol, specifically inhibit the activity of HMG-CoA reductase either by repression of the enzyme synthesis or by acceleration of the enzyme degradation. Several mevalonate-like fungal metabolites, e.g., compactin, competitively inhibit the activity of HMG-CoA reductase when they were incubated with cell cultures. Upon removal of these metabolites by washing the level of HMG-CoA reductase was found to increase by a still unknown mechanism. The objective of the present research project is to investigate the mechanisms by which oxygenated sterols, mevalonate-like fungal metabolites and other metabolic inhibitors affect the activity of HMG-CoA reductase.